Sickle cell disease (SCD) SCD is an autosomal recessive disorder characterized by hemolytic anemia and systemic inflammation that afflicts millions of people worldwide. Chronic pain is a hallmark of SCD. Intense ongoing pain and episodic pain starts early in life and increase in severity with age. The primary treatment for pai is opioids which have a variety of undesirable side effects such as respiratory depression and tolerance, and may contribute to organ damage. Although the pathophysiology of SCD is well understood, little is known about the mechanisms that mediate the pain in SCD. We will use an established mouse model of SCD, Berkley (BERK) mice, to study peripheral mechanisms of pain in SCD. These mice offer a unique advantage because of their similarity to human genetic, hematologic and pathological disease, including ongoing pain and hyperalgesia. Earlier studies and preliminary data show that these mice exhibit increased levels of cyclooxygenase (COX)-2 in the spinal cord and dorsal root ganglia (DRG) and a decrease in tissue content of 2-arachidonoyl-sn-glycerol (2-AG). COX-2 may contribute to pain through the formation of prostaglandins as well as prostaglandin-glycerol esters (PG-Gs) generated from the oxidation of 2-AG by COX-2 (e.g., PGE2-G) that sensitize nociceptors. Our general hypothesis is that PGE2-G contributes to pain in SCD. A multidisciplinary approach incorporating parallel biochemical, behavioral, cellular and electrophysiological studies in mice with SCD will test this hypothesis. We will determine whether PGE2-G is elevated in DRG and peripheral tissue in sickle mice (Aim 1), whether deceased production of PGE2-G decreases hyperalgesia (Aim 2), and whether PGE2-G sensitizes nociceptors in control mice and contributes to nociceptor sensitization in sickle mice (Aim 3). These studies will provide new insights into the peripheral mechanisms underlying pain in SCD, as well as new information on the role of PGE2-G in nociceptor sensitization, and may help identify new approaches for treating the chronic, debilitating pain in SCD.